- Novel triazines as potent and selective phosphodiesterase 10A inhibitors
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The identification of highly potent and orally active triazines for the inhibition of PDE10A is reported. The new analogs exhibit low-nanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired drug-like properties. Employing structure-based drug design approaches, we investigated the selectivity of PDE10A inhibitors against other known PDE isoforms, by methodically exploring the various sub-regions of the PDE10A ligand binding pocket. A systematic assessment of the ADME and pharmacokinetic properties of the newly synthesized compounds has led to the design of drug-like candidates with good brain permeability and desirable drug kinetics (t1/2, bioavailability, clearance). Compound 66 was highly potent for PDE10A (IC50 = 1.4 nM), demonstrated high selectivity (>200×) for the other PDEs, and was efficacious in animal models of psychoses; reversal of MK-801 induced hyperactivity (MED = 0.1 mg/kg) and conditioned avoidance responding (CAR; ID50 = 0.2 mg/kg).
- Malamas, Michael S.,Ni, Yike,Erdei, James,Fan, Kristi Yi,Parris, Kevin,Marquis, Karen L.,Grauer, Steve,Brennan, Julie,Navarra, Rachel,Graf, Radka,Harrison, Boyd L.,Robichaud, Albert,Pangalos, Menelas N.,Brandon, Nicholas J.,Stange, Hans,Schindler, Rudolf,Lankau, Hans-Joachim,Grunwald, Christian,Langen, Barbara,Egerland, Ute,Hage, Thorsten,Kronbach, Thomas,Hoefgen, Norbert
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p. 5876 - 5884,9
(2020/07/30)
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